tbuckley/cabot-search huggingface dataset:
Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous intraepithelial lesions
Authors: Ziena Abdulrahman, Natasja Hendriks, Arnold J Kruse, Antonios Somarakis, Anna J M van de Sande, Heleen J van Beekhuizen, Jurgen M J Piek, Noel F C C de Miranda, Loes F S Kooreman, Brigitte F M Slangen, Sjoerd H van der Burg, Peggy J de Vos van Steenwijk, Edith M G van Esch
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond. Methods Biopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning. Results The immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1 + /type 1 Tbet + ), M1-like macrophages (CD68 + CD163 - ) and dendritic cells (CD11c + ) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3 + FOXP3 + regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4 + T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p&lt;0.0001). Conclusion The capacity of cHSIL patients to respond to imiquimod is associated with a pre-existing coordinated local immune process, fostering an imiquimod-mediated increase in local T cell infiltration. The CIBI immunohistochemical biomarker has strong potential to select cHSIL patients with a high likelihood to experience a complete response to imiquimod immunotherapy.
Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model
Authors: Richard J Sové, Babita K Verma, Hanwen Wang, Won Jin Ho, Mark Yarchoan, Aleksander S Popel
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is the third-leading cause of cancer-related death worldwide. Most patients with HCC are diagnosed at an advanced stage, and the median survival for patients with advanced HCC treated with modern systemic therapy is less than 2 years. This leaves the advanced stage patients with limited treatment options. Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) or its ligand, are widely used in the treatment of HCC and are associated with durable responses in a subset of patients. ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also have clinical activity in HCC. Combination therapy of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) is the first treatment option for HCC to be approved by Food and Drug Administration that targets more than one immune checkpoints. Methods In this study, we used the framework of quantitative systems pharmacology (QSP) to perform a virtual clinical trial for nivolumab and ipilimumab in HCC patients. Our model incorporates detailed biological mechanisms of interactions of immune cells and cancer cells leading to antitumor response. To conduct virtual clinical trial, we generate virtual patient from a cohort of 5,000 proposed patients by extending recent algorithms from literature. The model was calibrated using the data of the clinical trial CheckMate 040 (ClinicalTrials.gov number, NCT01658878 ). Results Retrospective analyses were performed for different immune checkpoint therapies as performed in CheckMate 040. Using machine learning approach, we predict the importance of potential biomarkers for immune blockade therapies. Conclusions This is the first QSP model for HCC with ICIs and the predictions are consistent with clinically observed outcomes. This study demonstrates that using a mechanistic understanding of the underlying pathophysiology, QSP models can facilitate patient selection and design clinical trials with improved success.
Both APRIL and antibody-fragment-based CAR T cells for myeloma induce BCMA downmodulation by trogocytosis and internalization
Authors: Nicolas Camviel, Benita Wolf, Giancarlo Croce, David Gfeller, Vincent Zoete, Caroline Arber
Journal: Journal for ImmunoTherapy of Cancer (2022)

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only). Three new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell-target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo. APRIL-CAR T cells in a trimeric ligand binding conformation conferred fast but not sustained antitumor responses in vivo in mouse xenograft models. In vitro trimer-BBζ CAR T cells were more polyfunctional and formed stronger immune synapses than monomer-BBζ CAR T cells. After CAR T cell-myeloma cell contact, BCMA was rapidly downmodulated on target cells with all evaluated binding moieties. CAR T cells acquired BCMA by trogocytosis, and BCMA on MM cells was rapidly internalized. Since BCMA can be re-expressed during progression and persisting CAR T cells may not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell-MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo. Antitumor responses with APRIL-CAR T cells were fast but not sustained. Rapid BCMA downmodulation occurred independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM when targeting BCMA and can inform the development of improved treatment strategies.
Gut microbiome-depleting antibiotic regimens are not tolerated by all mouse strains: learn from (our) bitter experience
Authors: Andrew A Almonte, George Cavic, Teresa Neeman, Anselm Enders, Aude M Fahrer
Journal: Journal for ImmunoTherapy of Cancer (2022)

Why the gut microbiome is critical for the success of checkpoint inhibitor cancer therapy is a question that remains unanswered, but progress has slowed. We argue that this lack of advancement is due to an unappreciated biological detail. Here, we show that the antibiotic cocktail used in seminal publications-all of which have used the C57BL/6 mouse strain-are bitter and not tolerated by other common mouse strains (ie, BALB/c and DBA/2). We write to alert readers of this important biological limitation that must be considered when planning cancer experiments investigating the gut microbiota, to prevent the unnecessary dehydration of experimental animals, and to save our colleagues valuable experimental time and resources.
Estimating Savings Opportunities From Therapeutic Substitutions of High-Cost Generic Medications
Authors: Mariana P. Socal, Thomas Cordeiro, Gerard F. Anderson, Ge Bai
Journal: JAMA Network Open (2022)

Importance Use of generics is generally understood as a cost-saving practice. However, pharmacy benefit managers have an incentive to place higher-priced generic drugs on insurers’ drug formularies to profit by creating a large difference between the price negotiated with pharmacies and the price paid by insurers (what is known as spread pricing). Objective To examine price differentials and savings potential between high-cost generics and corresponding therapeutic alternatives of same clinical value and lower cost. Design, Setting, and Participants This cross-sectional analysis examined the top 1000 generics in Colorado’s all-payer claims database (CO-APCD) in 2019. High-cost generics and lower-cost generic therapeutic alternatives of same clinical value constituted the study sample. Data were analyzed from January 2019 to December 2019. Exposures Generic drug prices measured by transaction prices, average wholesale price (AWP), and national drug acquisition average cost (NADAC). Main Outcomes and Measures Price differentials between the high-cost generics and the corresponding therapeutic alternatives. Levels of discounts and savings that could be achieved if the high-cost generics had been substituted by their therapeutic alternatives. Results This cross-sectional study of the top 1000 CO-APCD generics identified 45 high-cost products that had lower-cost therapeutic alternatives of same clinical value. Overall, high-cost generics were 15.6 times more expensive than their therapeutic alternatives (median values). If the lower-cost alternatives had been used, total spending would have been reduced from $7.5 million to $873 711, resulting in 88.3% savings. Most substitutions (28 of 45 [62.2]%) involved different dosage forms or different strengths of the same drug and provided mean (SD) discounts of 94.9% (3.8%) and 77.1% (19.9%), respectively. Conclusions and Relevance In this study, replacing high-cost generics with lower-cost alternatives of same clinical value would produce savings of nearly 90%. Plan sponsors should be aware that some generics are associated with higher spending and should periodically review the specific products driving their generic drug spending. Substitution of high-cost generics may provide a simple pathway to offer the same therapeutic benefit at lower cost to patients and insurers.
COVID-19 Case Investigation and Contact Tracing in New York City, June 1, 2020, to October 31, 2021
Authors: Kathleen Blaney, Steffen Foerster, Jennifer Baumgartner, Megan Benckert, Janice Blake, Jackie Bray, Shadi Chamany, Katelynn Devinney, Annie Fine, Masha Gindler, Laura Guerra, Amanda Johnson, Chris Keeley, David Lee, Mia Lipsit, Sarah McKenney, Kavita Misra, Sarah Perl, Dana Peters, Madhury Ray, Eduardo Saad, Guajira Thomas, Lisa Trieu, Chi-Chi Udeagu, Julian Watkins, Marcia Wong, Lindsay Zielinski, Theodore Long, Neil M. Vora
Journal: JAMA Network Open (2022)

Contact tracing is a core strategy for preventing the spread of many infectious diseases of public health concern. Better understanding of the outcomes of contact tracing for COVID-19 as well as the operational opportunities and challenges in establishing a program for a jurisdiction as large as New York City (NYC) is important for the evaluation of this strategy.To describe the establishment, scaling, and maintenance of Trace, NYC's contact tracing program, and share data on outcomes during its first 17 months.This cross-sectional study included people with laboratory test-confirmed and probable COVID-19 and their contacts in NYC between June 1, 2020, and October 31, 2021. Trace launched on June 1, 2020, and had a workforce of 4147 contact tracers, with the majority of the workforce performing their jobs completely remotely. Data were analyzed in March 2022.Number and proportion of persons with COVID-19 and contacts on whom investigations were attempted and completed; timeliness of interviews relative to symptom onset or exposure for symptomatic cases and contacts, respectively.Case investigations were attempted for 941 035 persons. Of those, 840 922 (89.4%) were reached and 711 353 (75.6%) completed an intake interview (women and girls, 358 775 [50.4%]; 60 178 [8.5%] Asian, 110 636 [15.6%] Black, 210 489 [28.3%] Hispanic or Latino, 157 349 [22.1%] White). Interviews were attempted for 1 218 650 contacts. Of those, 904 927 (74.3%) were reached, and 590 333 (48.4%) completed intake (women and girls, 219 261 [37.2%]; 47 403 [8.0%] Asian, 98 916 [16.8%] Black, 177 600 [30.1%] Hispanic or Latino, 116 559 [19.7%] White). Completion rates were consistent over time and resistant to changes related to vaccination as well as isolation and quarantine guidance. Among symptomatic cases, median time from symptom onset to intake completion was 4.7 days; a median 1.4 contacts were identified per case. Median time from contacts' last date of exposure to intake completion was 2.3 days. Among contacts, 30.1% were tested within 14 days of notification. Among cases, 27.8% were known to Trace as contacts. The overall expense for Trace from May 6, 2020, through October 31, 2021, was approximately $600 million.Despite the complexity of developing a contact tracing program in a diverse city with a population of over 8 million people, in this case study we were able to identify 1.4 contacts per case and offer resources to safely isolate and quarantine to over 1 million cases and contacts in this study period.
Germline variants of IGHV3-53 / V3-66 are determinants of antibody responses to the BNT162b2 mRNA COVID-19 vaccine
Authors: Yoichi Mashimo, Keiko Yamazaki, Takahiro Kageyama, Shigeru Tanaka, Toshibumi Taniguchi, Kazuyuki Matsushita, Hidetoshi Igari, Hideki Hanaoka, Koutaro Yokote, Hiroshi Nakajima, Yoshihiro Onouchi
Journal: Journal of Infection (2022)
Re: Hilda A. de Barros, Matthias N. van Oosterom, Maarten L. Donswijk, et al. Robot-assisted Prostate-specific Membrane Antigen–radioguided Salvage Surgery in Recurrent Prostate Cancer Using a DROP-IN Gamma Probe: The First Prospective Feasibility Study. Eur Urol 2022;82:97–105
Authors: Xiangyang Yao, Chen Duan, Bo Li, Xiaoliang Wu, Hua Xu
Journal: European Urology (2022)
Mechanisms for Reduced Fibrin Clot Formation on Liquid‐Infused Surfaces (Adv. Healthcare Mater. 21/2022)
Authors: Jun Ki Hong, Alexander M. Ruhoff, Kavya Mathur, Chiara Neto, Anna Waterhouse
Journal: Advanced Healthcare Materials (2022)

Biomaterial Thrombosis In article 2201360, Anna Waterhouse and co-workers demonstrate enhanced mobility at the blood–liquid interface as a key mechanism by which liquid-immobilized surfaces (LIS) achieve their anti-thrombogenic behavior. Interfacial mobility is a physical mechanism capable of reducing adhesion and preventing thrombosis which could reveal new insights for the design of liquid-infused surfaces for anti-thrombogenic, blood-contacting medical devices and anti-fouling applications, more broadly.
D–A Type NIR‐II Organic Molecules: Strategies for the Enhancement Fluorescence Brightness and Applications in NIR‐II Fluorescence Imaging‐Navigated Photothermal Therapy (Adv. Healthcare Mater. 21/2022)
Authors: Yan Chen, Shangyu Chen, Haoli Yu, Yuesong Wang, Mengyuan Cui, Peng Wang, Pengfei Sun, Min Ji
Journal: Advanced Healthcare Materials (2022)

Photothermal Therapy In article 2201158 by Peng Wang, Pengfei Sun, Min Ji, and co-workers, some approaches to the development and design strategies of D–A type small molecules and conjugated polymers for the enhancement of fluorescence brightness are systemically introduced. Meanwhile, some applications of photothermal therpy (PTT) and PTT-based combination therapies assisted by NIR-II FI-based single or multiimaging technologies are classified and represented in detail. Finally, the current issues and challenges of NIR-II organic molecules in NIR-II FI-navigated PTT are summarized and discussed.
Low Apgar score and asphyxia complications at birth and risk of longer-term cardiovascular disease: a nationwide population-based study of term infants
Authors: Neda Razaz, Mikael Norman, Tobias Alfvén, Sven Cnattingius
Journal: The Lancet Regional Health - Europe (2022)

Most follow-up studies have focused on the long-term consequences of asphyxia at birth on the brain. The aim of this study was to investigate associations between low Apgar score and asphyxia-related complications and subsequent risks of cardiovascular diseases (CVD) in childhood and early adulthood.This population-based cohort study included 2,826,424 non-malformed singleton births, born at term (≥37 weeks' gestation) between 1988 and 2018 in Sweden. Primary exposure was a composite of asphyxia-related complications, defined as a) Apgar score 0-3 at 1-min; or b) Apgar score 0-3 at 5-min; or c) neonatal seizures (including hypoxic ischemic encephalopathy). Using Cox regression, we estimated the risk of CVD after 1 year of age, defined as stroke, coronary heart disease, heart failure, and atrial fibrillation.Overall, there were 4165 cases with cardiovascular diseases. Individuals with asphyxia-related complications had adjusted hazard ratios (95% confidence intervals) of 1.90 (1.54 to 2.34) for cardiovascular disease, 2.29 (1.74 to 3.03) for stroke, 2.17 (1.37 to 3.42) for heart failure, and 1.38 (0.87 to 2.17) for atrial fibrillation. Hazard ratios for CVD were elevated among individuals with Apgar score 0-3 at 1 and 5 min, and those with neonatal seizures. Compared with unexposed individuals, neonatal seizures were associated with 5 times higher rates of stroke and heart failure, respectively.Asphyxia-related complications and its neonatal complications, especially low Apgar score and neonatal seizures, are associated with increased risks of CVD in childhood and early adulthood, although the absolute risk of CVD is low in young age.Swedish Research Council and the Swedish Heart-Lung Foundation.
Complementary and Synergistic Design of Bi‐Layered Double Hydroxides Modified Magnesium Alloy toward Multifunctional Orthopedic Implants
Authors: Dongdong Zhang, Mei Li, Ru Xu, Juning Xie, Yu Zhang, Shi Qian, Yuqin Qiao, Feng Peng, Xuanyong Liu
Journal: Advanced Healthcare Materials (2022)

Magnesium (Mg)-based alloys have been regarded as promising implants for future clinic orthopedics, however, how to endow them with good anti-corrosion and biofunctions still remains a great challenge, especially for complicated bone diseases. Herein, three transition metals (M = Mn, Fe, and Co)-containing layered double hydroxides (LDH) (LDH-Mn, LDH-Fe, and LDH-Co) with similar M content are prepared on Mg alloy via a novel two-step method, then systematic characterizations and comparisons are conducted in detail. Results showed that LDH-Mn exhibited the best corrosion resistance, LDH-Mn and LDH-Co possessed excellent photothermal and enzymatic activities, LDH-Fe revealed better cytocompatibility and antibacterial properties, while LDH-Co demonstrated high cytotoxicity. Based on these results, an optimized bilayer LDH coating enriched with Fe and Mn (LDH-MnFe) from top to bottom have been designed for further in vitro and in vivo analysis. The top Fe-riched layer provided biocompatibility and antibacterial properties, while the bottom Mn-riced layer provided excellent anti-corrosion, photothermal and enzymatic effects. In addition, the released Mg, Fe, and Mn ions have a positive influence on angiogenesis and osteogenesis. Thus, the LDH-MnFe showed complementary and synergistic effects on anti-corrosion and multibiofunctions (antibacteria, antitumor, and osteogenesis). The present work offers a novel multifunctional Mg-based implant for treating bone diseases.
In vitro activity of imipenem/relebactam, meropenem/vaborbactam and comparators against Pseudomonas aeruginosa in Taiwan: Results from the Study for Monitoring Antimicrobial Resistance Trends (SMART) in 2020
Authors: Yuag-Meng Liu, Wen-Chien Ko, Mao-Wang Ho, Yu-Lin Lee, Po-Ren Hsueh
Journal: Journal of Infection (2022)
Improving systemic corticosteroid stewardship in asthma
Authors: William W. Busse
Journal: European Respiratory Journal (2022)

<b>New evidence in this issue of the <i>ERJ</i> indicates that the previous duration and cumulative dose of oral corticosteroids influence the likelihood to achieve corticosteroid tapering after initiating IL-5/IL5R biologics for severe asthma</b>https://bit.ly/3RONCRL
A Review of Common Hand Conditions—Reply
Authors: Kelly Bettina Currie, Kashyap Komarraju Tadisina, Susan E. Mackinnon
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A Review of Common Hand Conditions
Authors: Akira Wiberg, David Ring, Dominic Furniss
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal